Pregnancy-induced hypertension, or preeclampsia (PE), is a complex vascular disorder that causes significant morbidity and mortality in women. Characterized by an inability of fetal placental cells (trophoblasts) to properly invade and remodel maternal blood vessels into low resistance conduits, it can also result in fetal growth restriction. Since delivery of the placenta is the only definitive cure, it is a leading cause of preterm birth. Because no unifying theory explains its origins, it remains impossible to predict or prevent. Previously, we characterized the critical role of the transcriptional response to oxygen deprivation during normal placental development. Here, we investigate two novel theories regarding the role of Hypoxia-inducible Factor (HIF), an oxygen sensitive transcriptional regulator, during pathological states that compromise placental vascularization. First, we test the hypothesis that HIF can be induced in trophoblasts by changes in the composition of the their extracellular matrix (ECM). We show that altering the ECM upon which trophoblast stem cells (TSCs) are cultured triggers differentiation-dependent HIF activation via pathways that intersect with those responsible for oxygen sensing. Our preliminary observations therefore suggest that HIF can integrate positional and metabolic cues at the maternal-fetal interface to regulate trophoblast differentiation along lines that promote placental perfusion. As compromised oxygen delivery and ECM remodeling are frequently associated with impaired trophoblast differentiation and endovascular invasion in the setting of PE, our studies will help unify these disparate threads of inquiry. To understand the mechanisms involved, we outline a research program designed to identify the molecular pathways linking oxygen and ECM-dependent HIF activation and cell fate determination in the placenta. Second, we provide compelling evidence for a canonical target gene independent role for HIF during trophoblast differentiation, dramatically altering our view of HIF biology during development. We propose to utilize genetically modified TSCs, next generation sequencing technologies, and a human placenta tissue bank to test the hypothesis that atypical HIF-target genes regulate mouse and human placentation, and that this process is disrupted in PE. Importantly, the combination of directed and unbiased approaches designed to dissect the pathways involved may lead to novel pharmacological targets to prevent or treat this intractable disorder.